This invention relates to certain novel triazepines having neurotrophic activity. These compounds, along with related compositions and methods, are useful in the treatment and prevention of neuronal disorders such as Parkinson""s disease, Alzheimer""s disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, and Bell""s palsy.
Neurodegenerative diseases constitute a major threat to public health throughout the world. One of the most serious of such diseases is Alzheimer""s disease (AD), a major cause of dementia in aged humans and the fourth most common medical cause of death in the United States. In the U.S., it is estimated that AD afflicts two to three million individuals overall, and more than 5% of the population over the age of 65. Although the exact etiology of AD remains to be defined, the disease is characterized by the presence of a large number of amyloid plaques and neurofibrillary tangles in regions of the brain involved in cognitive function, and degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas. Currently, there are no effective therapies for AD (Brinton, R. D. and Yamazaki, R. S., Pharm. Res., 1998, 15:386-98).
Similar to AD, Parkinson""s Disease (PD) is a progressive degenerative disease of the central nervous system (CNS). The lifetime incidence of the disease is approximately 2% in the general population. In PD, degeneration of the dopaminergic neurons of the substantia nigra leads to a decrease in dopamine levels in the region of the brain controlling voluntary movement, the corpus striatum. Therefore, standard treatments have focused on the administration of agents, like L-dopa and bromocriptine, which replenish dopamine levels in the affected areas of the brain. Dopaminergic regimens lose their efficacy, however, as nerve cells continue to die and the disease progresses. At the same time the involuntary tremors seen in the early stages of PD advance to periods of difficult movement and, ultimately, to immobility. Therefore, alternative therapies are actively being sought (Pahwa, R. and Koller, W. C., Drugs Today, 1998, 34:95-105).
Neurodegenerative diseases of the somatosensory nervous system also constitute a class of debilitating and potentially lethal conditions. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive degeneration of the upper and lower motor neurons. Although the precise etiology of ALS is unknown, popular theories suggest that excitotoxicity and/or oxidative stress are contributing factors. Riluzole is the first drug approved and marketed for ALS. It possesses antiexcitotoxic properties and has been shown to increase the rate of survival of ALS patients. However, the drug is not a cure, and clinical trials of alternative agents are currently underway (Louvel, E., Hugon, J. and Doble, A., Trends Pharmacol. Sci., 1997, 18:196-203).
Peripheral neuropathies are secondary to a number of metabolic and vascular conditions. In particular, approximately 30% of patients with diabetes mellitus suffer from some form of peripheral neuropathy that may affect either the small myelinated fibers, causing loss of pain and temperature sensation, or the large fibers, causing motor or somatosensory defects. Pharmacotherapeutic intervention tends to be symptomatic, and the best approach to treatment and prevention remains the maintenance of normal blood glucose levels through diet and insulin administration (Biessels, G. J. and Van Dam, P. S., Neurosci. Res. Commun., 1997, 20:1-10).
A considerable body of evidence now suggests that deficiencies in the levels of certain proteinaceous growth factors, or neurotrophic factors, may play key pathoetiological roles in both peripheral and central neurodegenerative diseases (Tomlinson et al., Diabetes, 1997, 46(suppl. 2):S43-S-49; Hamilton, G. S., Chem. Ind., (London) 1998, 4:127-132; Louvel et al., Trends Pharmacol. Sci., 1997, 18:196-203; Ebadi et al., Neurochem. Int., 1997, 30:347-374).
These neurotrophic factors can be divided into two structural classes: 1) the neurotrophins, including nerve growth factor (NGF); glial cell-derived neurotrophic growth factor (GDNF); brain-derived neurotrophic factor (BDNF); neurotrophin 3 (NT-3); neurotrophin 4/5 (NT-4/5); neurotrophin 2 (NT-2); and ciliary neurotrophic factor (CNTF) which is related to the cytokine family of molecules. All neurotrophic factors promote neurite outgrowth, induce differentiation, and suppress programmed cell death or apoptosis in specific subpopulations of peripheral and central neurons. For example, NGF exerts trophic effects on sympathetic and sensory neurons of the dorsal root ganglion and cholinergic neurons of medial septum in the CNS, suggesting potential therapeutic utility in AD. CNTF has trophic actions on a broad cross-section of neurons, including parasympathetic, sensory, sympathetic, motor, cerebellar, hippocampal, and septal neurons. Of particular interest is the fact that CNTF partially prevents the atrophy of skeletal muscle following the formation of nerve lesions but has no effect on innervated muscle, indicating that CNTF is primarily operative in the pathological state. As a result, CNTF is currently being evaluated for its effects in musculoskeletal diseases like ALS.
The clinical utility of proteinaceous neurotrophic agents is severely hampered by their limited bioavailability, especially in the CNS. This necessitates the administration of these agents directly into the brain to induce a therapeutic effect. Administration to the brain can be a relatively hazardous and a cumbersome route of administration.
Protein based compounds currently in clinical use as neurotrophic agents cannot be administered orally and otherwise show poor bioavailability except when administered intracerebroventricularly (ICV) for a CNS indication or intravenously for peripheral nerve dysfunctions such as diabetic neuropathy or Bell""s palsy. Accordingly, there is a clear need for bioavailable small molecule mimetics of neurotrophic factors that are orally bioavailable and can readily penetrate the blood-brain barrier.
Great efforts have been made to identify small molecules having neurotrophic activity, but all such compounds reported so far are structurally dissimilar to triazepines.
This invention provides novel triazepine compounds having surprising neurotrophic activity. Demonstrated to have these biological activities by in vitro and in vivo assays described hereinafter are the compounds of the present invention as shown in Formula I and II: 
or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, and R4 are independently selected from hydrogen, C1-C10 alkyl, aryl, and heterocyclyl, or R1, the nitrogen atom attached to R1, and R2 together form a 4- to 8-membered heterocycle having 1 to 4 heteroatoms selected from the group consisting of S, O, and N; and
R5 is selected from C1-C10 alkyl, aryl, and heterocyclyl, or R1, the nitrogen atom attached to R1, and R2 together form a 4- to 8-membered heterocycle having 1 to 4 heteroatoms selected from the group consisting of S, O, and N.
This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier, as well as related synthetic methods.
This invention further provides a method of treating a subject suffering from a condition characterized by neuronal damage caused by disease or trauma, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
This invention still further provides a method of inhibiting in a subject the onset of a condition characterized by neuronal damage caused by disease or trauma, which method comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.